Acid, helicobacter and immunity: a new paradigm for oesophagogastric cancer.

Epidemiological evidence has clearly shown a highly significant relationship between Helicobacter pylori infection and the development of duodenal ulcer and distal gastric adenocarcinoma. Despite H. pylori being a common aetiological factor for both disorders, the two disease phenotypes are virtually mutually exclusive. This indicates that the host response to infection has a pivotal role in determining outcome; these disease phenotypes relate to the effect of infection on gastric acid secretion, duodenal ulcer being closely related to sustained acid secretion whereas gastric cancer follows gastric atrophy and impaired gastric acid secretion. Cancer at the oesophageal junction and that associated with Barrett's oesophagus is now the most rapidly increasing tumour in the gastrointestinal tract. The challenge for the next millennium, therefore, is to try and develop methods for identifying patients at risk of developing oesophagogastric cancer. A common feature in the pathogenesis of both gastric and oesophageal adenocarcinoma is inflammation presenting clinically as gastritis and oesophagitis. The pathway from gastritis to gastric atrophy, dysplasia and carcinoma is thought to be a multi-step process, probably triggered by free radicals within the gastric epithelium and increased exposure to luminal carcinogens. However, it has been unclear as to which aspect of the host response determines whether an individual will move along the neoplasia pathway. Recent work has shown that qualitative aspects of the immune environment in the stomach may account for a substantial part of the phenotypic divergence following H. pylori infection. Interleukin-1 beta polymorphisms relate closely to the propensity for an individual to develop distal gastric cancer and maybe useful for predicting risk in family members. In Barrett's oesophagus, we have recently shown that the immune environment may also be important in determining whether an individual will develop cancer. Although we did not find that Barrett's oesophagus was a profoundly inflammatory condition (unlike esophagitis in the squamous epithelium), where there was evidence of inflammation it was qualitatively different from that of oesophagitis in that a Th-2 response with increased expression of IL-4 predominated in Barrett's, whereas a Th-1 proinflammatory response characterised oesophagitis in squamous epithelium. It seems likely that the specific immune environment within Barrett's metaplasia may be an important driver towards dysplasia and carcinoma. Thus, the immune environment in the stomach and esophagus may be critical in determining whether an individual is at risk of developing neoplastic complications of H. pylori infection and gastroesophageal reflux. Identification of the genetic factors which underpin these responses may ultimately result in development of methods to identify individuals at high risk.     

Substance use in remand prisoners: a consecutive case study.

OBJECTIVES: To determine the prevalence of drug and alcohol use among newly remanded prisoners, assess the effectiveness of prison reception screening, and examine the clinical management of substance misusers among remand prisoners. DESIGN: A consecutive case study of remand prisoners screened at reception for substance misuse and treatment needs and comparison of findings with those of prison reception screening and treatment provision. SETTING: A large adult male remand prison (Durham). SUBJECTS: 548 men aged 21 and over awaiting trial. MAIN OUTCOME MEASURES: Prevalence of substance misuse; treatment needs of substance misusers; effectiveness of prison reception screening for substance misuse; provision of detoxification programmes. RESULTS: Before remand 312 (57%) men were using illicit drugs and 181 (33%) met DSM-IV drug misuse or dependence criteria; 177 (32%) men met misuse or dependence criteria for alcohol. 391 (71%) men were judged to require help directed at their drug or alcohol use and 197 (36%) were judged to require a detoxification programme. The prison reception screen identified recent illicit drug use in 131 (24%) of 536 men and problem drinking in 103 (19%). Drug use was more likely to be identified by prison screening if an inmate was using multiple substances, using opiates, or had a diagnosis of abuse or dependence. 47 (9%) of 536 inmates were prescribed treatment to ease the symptoms of substance withdrawal. CONCLUSIONS: The prevalence of substance misuse in newly remanded prisoners is high. Prison reception health screening consistently underestimated drug and alcohol use. In many cases in which substance use is identified the quantities and numbers of different substances being used are underestimated. Initial management of inmates identified by prison screening as having problems with dependence producing substances is poor. Few receive a detoxification programme, so that many are left with the option of continuing to use drugs in prison or facing untreated withdrawal.     

Association of human papillomavirus with prostate cancer: analysis of a consecutive series of prostate biopsies

The study purpose was to investigate the association of human papillomavirus (HPV) infection with prostate cancer. The presence and type of HPV DNA were investigated by polymerase chain reaction in the preservation fluid of 60 consecutive prostate core biopsies (29 benign, 31 malignant). The material was inadequate (no DNA found at beta-globin testing) in four benign and five cancer biopsies. HPV DNA was found in 17 of 26 (65.3%) cancer and 12 of 25 (48.0%) benign biopsies (chi2 = 0.94, p = 0.33). High-risk HPV type positivity was observed in 14 of 26 (53.8%) cancer and in five of 25 (20.0%) benign biopsies (chi2 = 4.38, p = 0.03). Twenty-three of 29 cases were positive at L1 region testing with MY09/11 primers; testing with primers directed to the E6/E7 region revealed six further HPV-positive cases (four cancer, two benign). The presence of HPV in prostate tissue suggests a possible reservoir for sexual transmission of types with oncogenic potential. Our findings also suggest a possible role of high-risk HPV infection in the etiology of prostate cancer and encourage further research into this issue.     

Approach to diagnosis and pathological examination in bronchial Dieulafoy disease: a case series

Background

We previously observed that allergen-exposed mice exhibit remodeling of large bronchial-associated blood vessels. The aim of the study was to examine whether vascular remodeling occurs also in vessels where a spill-over effect of bronchial remodeling molecules is less likely.

Methods

We used an established mouse model of allergic airway inflammation, where an allergic airway inflammation is triggered by inhalations of OVA. Remodeling of bronchial un-associated vessels was determined histologically by staining for α-smooth muscle actin, procollagen I, Ki67 and von Willebrand-factor. Myofibroblasts were defined as and visualized by double staining for α-smooth muscle actin and procollagen I. For quantification the blood vessels were divided, based on length of basement membrane, into groups; small (≤250 μm) and mid-sized (250–500 μm).

Results

We discovered marked remodeling in solitary small and mid-sized blood vessels. Smooth muscle mass increased significantly as did the number of proliferating smooth muscle and endothelial cells. The changes were similar to those previously seen in large bronchial-associated vessels. Additionally, normally poorly muscularized blood vessels changed phenotype to a more muscularized type and the number of myofibroblasts around the small and mid-sized vessels increased following allergen challenge.

Conclusion

We demonstrate that allergic airway inflammation in mice is accompanied by remodeling of small and mid-sized pulmonary blood vessels some distance away (at least 150 μm) from the allergen-exposed bronchi. The present findings suggest the possibility that allergic airway inflammation may cause such vascular remodeling as previously associated with lung inflammatory conditions involving a risk for development of pulmonary hypertension.     

Examining methodology to identify patterns of consulting in primary care for different groups of patients before a diagnosis of cancer: An exemplar applied to oesophagogastric cancer

BackgroundCurrent methods for estimating the timeliness of cancer diagnosis are not robust because dates of key defining milestones, for example first presentation, are uncertain. This is exacerbated when patients have other conditions (multimorbidity), particularly those that share symptoms with cancer. Methods independent of this uncertainty are needed for accurate estimates of the timeliness of cancer diagnosis, and to understand how multimorbidity impacts the diagnostic process.MethodsParticipants were diagnosed with oesophagogastric cancer between 2010 and 2019. Controls were matched on year of birth, sex, general practice and multimorbidity burden calculated using the Cambridge Multimorbidity Score. Primary care data (Clinical Practice Research Datalink) was used to explore population-level consultation rates for up to two years before diagnosis across different multimorbidity burdens. Five approaches were compared on the timing of the consultation frequency increase, the inflection point for different multimorbidity burdens, different aggregated time-periods and sample sizes.ResultsWe included 15,410 participants, of which 13,328 (86.5 %) had a measurable multimorbidity burden. Our new maximum likelihood estimation method found evidence that the inflection point in consultation frequency varied with multimorbidity burden, from 154 days (95 %CI 131.8–176.2) before diagnosis for patients with no multimorbidity, to 126 days (108.5–143.5) for patients with the greatest multimorbidity burden. Inflection points identified using alternative methods were closer to diagnosis for up to three burden groups. Sample size reduction and changing the aggregation period resulted in inflection points closer to diagnosis, with the smallest change for the maximum likelihood method.DiscussionExisting methods to identify changes in consultation rates can introduce substantial bias which depends on sample size and aggregation period. The direct maximum likelihood method was less prone to this bias than other methods and offers a robust, population-level alternative for estimating the timeliness of cancer diagnosis.     

Delay in diagnosis of homocystinuria: retrospective study of consecutive patients.

OBJECTIVE: To assess the causes for delay in the diagnosis of homocystinuria. DESIGN: Clinical and laboratory data were collected from patients diagnosed as having homocystinuria due to cystathionine synthase deficiency, with special reference to the ages at which the patients had their first major signs of the disease, ectopia lentis was established, and homocystinuria was diagnosed. SETTING: University hospital in the Netherlands. SUBJECTS: 34 patients (18 males) in whom homocystinuria due to cystathionine synthase deficiency was diagnosed in the period 1970-94. RESULTS: Among 34 consecutively detected homocystinuria patients the mean age at diagnosis of homocystinuria was 24 (range 1-61) years. Despite frequent ocular manifestations, serious complications in the vascular, skeletal, and central nervous systems, and repeated examinations performed in these patients by clinicians of various disciplines, there was a mean delay of 11 (0-43) years between the first major signs of the disease (at mean age 13 (1-40) years) and the ultimate diagnosis of homocystinuria. Even when ectopia lentis was diagnosed (in 26 (76%) patients, mean age 18 (1-50) years), this did not lead to adequate biochemical analysis for homocystinuria at the time of detection, causing a mean diagnostic delay of 8 (0-24) years in these patients. CONCLUSIONS: Three factors should have precipitated the diagnosis of homocystinuria: early recognition that unusual myopia (high, very high, abnormal progressive, or at young age) was caused by subluxation of the ocular lenses; awareness that the occurrence of myopia combined with systemic complications ("myopia plus") might be due to homocystinuria; and appropriate biochemical investigations carried out in patients with ectopia lentis and in their siblings.     

Esophageal cancer in young people: a case series of 109 cases and review of the literature

Certain geographically distinct areas of the world have very high rates of esophageal cancer (EC). Previous studies have identified western Kenya as a high risk area for EC with an unusual percentage of cases in subjects 30 years of age or younger. To better understand EC in these young patients, we abstracted available data on all 109 young patients diagnosed with EC at Tenwek Hospital, Bomet District, Kenya from January 1996 through June 2009, including age at diagnosis, sex, ethnicity, tumor histology, residence location, and medical interventions. We also attempted to contact all patients or a family member and obtained information on ethnicity, tobacco and alcohol use, family history of cancer, and survival. Sixty (55%) representatives of the 109 young patients were successfully interviewed. The median survival time of these 60 patients was 6.4 months, the most common tumor histology was esophageal squamous cell carcinoma (ESCC) (98%), the M:F ratio was 1.4∶1, and only a few subjects used tobacco (15%) or alcohol (15%). Seventy-nine percent reported a family history of cancer and 43% reported having a family history of EC. In summary, this case series describes the largest number of young EC patients reported to date, and it highlights the uniqueness of the EC experience in western Kenya.     

Analysis of risks and aesthetics in a consecutive series of tissue expansion breast reconstructions.

A consecutive series of 73 patients underwent tissue expansion for breast reconstruction between 1980 and 1986. The cases were reviewed, and preoperative risk factors, postoperative complications, and aesthetic results were assessed. Cigarette smoking correlated with a higher incidence of complications and unfavorable results. Similar correlations were found among patients with histories of significant medical disorders or alcohol abuse, although patient numbers were small in these categories. Subpectoral and suprapectoral placement of expanders yielded similar complication rates and aesthetic results. Surgical techniques contributing to improved aesthetic results are described.     

Radial nerve palsy in the newborn: a case series

Background:

Peripheral nerve palsies of the upper extremities presenting at birth can be distressing for families and care providers. It is therefore important to be able to identify patients whose diagnosis is compatible with full recovery so that their families can be reassured.

Methods:

We conducted a retrospective review of all infants presenting with weakness of the upper extremity to our clinic between July 1995 and September 2009. We also conducted a review of the current literature.

Results:

During the study period, 953 infants presented to our clinic. Of these patients, 25 were identified as having isolated radial nerve palsy (i.e., a radial nerve palsy in isolation with good shoulder function and intact flexion of the elbow). Seventeen infants (68.0%) had a subcutaneous nodule representing fat necrosis in the inferior posterolateral portion of the affected arm. Full recovery occurred in all patients within a range of one week to six months, and 72.0% of the patients (18/25) had fully recovered by the time they were two months old.

Interpretation:

Although the outcome of obstetrical brachial plexus palsy is highly variable, isolated radial nerve palsy in the newborn carries a uniformly favourable prognosis.Peripheral nerve palsies in the newborn are uncommon and usually involve the brachial plexus or facial nerve.¹ Isolated radial nerve palsy in the newborn is a rare phenomenon and may be misdiagnosed as obstetrical brachial plexus palsy. It is important to differentiate between these two conditions, as the management and prognosis of each diagnosis are different. Over the last three decades, multiple reports of small numbers of patients with radial nerve palsy present at birth have been published.^2–6 This paper presents the largest single series of this lesion currently documented in the literature.     

BRCA1 mutations and polymorphisms in a hospital-based consecutive series of breast cancer patients from Apulia, Italy

INTRODUCTION: Hereditary breast cancer has been partly attributed to germline mutations in the BRCA1 gene that are deleterious for BRCA1 protein activity. This paper analyzes the incidence and characteristics of detectable BRCA1 mutations and polymorphisms in a hospital-based consecutive series of breast cancer patients from southern Italy to investigate the incidence and the association of these molecular alterations with breast cancer biology and family history. METHODS: One hundred cases with familial characteristics were selected from a consecutive series of 511 patients with a first diagnosis of breast cancer. DNA from peripheral blood was screened for whole BRCA1 gene mutations utilizing dHPLC as a pre-screening analysis and automatic DNA sequencing for the identification of specific alterations. RESULTS: In the overall series of 511 patients, 100 had a family history of breast cancer and were investigated for BRCA1 mutations. Two types of BRCA1 mutations were identified, 5382insC in six cases and 4566delA in one case. The 5382insC mutation was present in two out of six cases with ovarian cancer while 4566delA in one case of male cancer. The most frequent missense polymorphisms were E1038G, P871L, K1183R in exon 11, S1613G, M1652I in exon 16 and D1778G in exon 22. Confirming what found in previous studies, patients in whom pathological BRCA1 mutations were detected had early-onset breast cancer (p=0.05), positive nodal status (p=0.05), lower ER (p=0.02) and PgR (p=0.01) content. Interestingly, the K1183R polymorphism and, less strongly, S1613G polymorphism were associated to mutational risk (K1183R: OR 0.1 p=0.03; S1613G: OR 2.7 p=0.08). CONCLUSION: Mutations in the BRCA1 gene are frequent also in our consecutive series of patients from southern Italy. An association between two detected single nucleotide polymorphisms (SNPs) and BRCA1 mutational risk was ascertained. Finally, we confirm the fact that peculiar clinical-pathological features seem to characterize patients with a family history of breast cancer and BRCA1 alterations.     

Prevalence of mental disorder in remand prisoners: consecutive case study.

OBJECTIVE: To define the prevalence of mental disorder and need for psychiatric treatment in new remand prisoners and to determine to what extent these are recognised and addressed in prison. DESIGN: Study of consecutive male remand prisoners at reception using a semistructured psychiatric interview. SETTING: Large remand prison for men (HMP Durham). SUBJECTS: 669 men aged 21 years and over on remand, awaiting trial. MAIN OUTCOME MEASURES: Prevalence of mental disorder at reception, prisoners need for psychiatric treatment, identification of mental disorder by prison reception screening, and numbers placed appropriately in the prison hospital. RESULTS: 148 (26%) men had one or more current mental disorders (excluding substance misuse) including 24 who were acutely psychotic. The prison reception screening identified 34 of the men with mental disorder and six of those with acute psychosis. 168 men required psychiatric treatment, 50 of whom required urgent intervention; 16 required immediate transfer to psychiatric hospital. Of these 50, 17 were placed on the hospital wing because of mental disorder recognised at prison screening. CONCLUSION: Not only is the prevalence of mental disorder, in particular severe mental illness, high in this population, but the numbers identified at reception are low and subsequent management in prison is poor.